November 2015, Vol. 2, No. 6

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High-Dose Interleukin-2 as a Second-Line Option in Metastatic Melanoma

Interview with the Innovators

An Interview with Elizabeth I. Buchbinder, MD, of Dana-Farber Cancer Institute

Many patients with melanoma have benefited from the recent employment of therapeutic agents targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) such as ipilimumab and the immune checkpoint blockade (ICB) agents targeting the programmed death-1/ligand 1 (PD-1/PD-L1) pathway. As more patients are treated with CTLA-4–targeting agents and ICB as frontline therapy, it becomes increasingly important to understand optimal sequencing of immunotherapeutic agents. To begin addressing this question, Elizabeth I. Buchbinder, MD, Dana-Farber Cancer Institute, conducted a retrospective study addressing the safety and efficacy of high-dose aldesleukin (HD IL-2) as second-line therapy for patients who previously received a CTLA-4–targeting agent or an ICB in metastatic melanoma (mM) or metastatic renal cell carcinoma (mRCC). HD IL-2 was selected as the focus of the current study as it received FDA approval for the frontline treatment of mM and mRCC based on its ability to produce durable responses in a subset of patients.

At the recent American Society of Clinical Oncology (ASCO) Annual Meeting, Dr Buchbinder presented results from this study, and the publishers of ITO had the opportunity to speak with her about this important work.

ITO There was much discussion at ASCO this year about the impact of the ICB therapies in both mM and mRCC. Can you discuss how treatments have evolved over the past several years in these 2 disease states?

Dr Buchbinder
We are experiencing a major shift in the treatment landscape in both mM and mRCC. In both diseases, ICB therapies have moved to the forefront when deciding which immunotherapy to use as a first-line therapy. In mM, 3 new ICB agents have been approved in the past 4 years: ipilimumab, nivolumab, and pembrolizumab. Nivolumab and pembrolizumab have been approved within the past year.

Meanwhile, in mRCC, we have yet to see survival data on these agents, even though we have seen some evidence of activity in this patient population.

Due to the widespread use of ICB agents in both of these patient populations, particularly in mM, many oncologists are now seeking options for patients who fail on ICB therapy. Other immunotherapies, such as HD IL-2, continue to be an effective option for this patient population.

ITO Given the plethora of options patients have for therapy, what factors have to be taken into consideration when determining which therapy is most appropriate for each patient?

Dr Buchbinder The factors we need to consider when determining the most appropriate immunotherapy for a patient are the aggressiveness of their malignancy, underlying autoimmune conditions, and overall performance status.

In these mM and mRCC patient populations, the aggressiveness of their tumors plays a key role in determining immunotherapy sequencing. We must take into consideration whether the patient has time for a delayed approach or if their malignancy shows very aggressive symptoms requiring immediate action.

If patients have an autoimmune condition, this can interfere with immunotherapy. These patients might not tolerate these agents as well, although we have given them safely to select patients.

We must also evaluate the patients’ overall performance status. If patients have comorbidities, this will impact their tolerance of these immunotherapies regardless of first- or second-line sequence order.

ITO Combining and sequencing of therapy seems to be a hot topic at the moment, in light of the fact that a significant number of patients will not respond to initial treatment with ICB. You presented data on patients treated with HD IL-2 after ICB in both mM and mRCC. What prompted you to look at these populations?

Dr Buchbinder HD IL-2 originally received FDA approval for the frontline treatment of mM and mRCC based on its ability to produce durable complete responses in a subset of patients. Recently, ICB agents have been deployed and tested in these settings. As more patients are treated with ICB as frontline therapy, it has become increasingly important for us to understand if HD IL-2 is safe and efficacious as a second-line therapy, specifically if these patients would experience increased toxicities due to initial ICB treatment.

ITO Can you describe the importance of your findings?

Dr Buchbinder Our ASCO data revealed a plethora of ICB sequencing considerations for mM and mRCC. The most important takeaway from our ASCO data is that we discovered there were no increased toxicities for both mM and mRCC patients who received HD IL-2 after treatment with CTLA-4 and PD-1/PD-L1 immune checkpoint blockades. Not only is HD IL-2 safe for those patients who do not respond to ICB, but efficacy was also observed.

In patients who received ipilimumab before HD IL-2, we saw no change in efficacy and no spike in immune-related events. The immune toxicity in these patients was manageable. In patients who received anti–PD-1 therapy before HD IL-2, we saw quite a few durable responses and patients with stable disease. These results are very similar to giving HD IL-2 frontline.

These data suggest that there may be a potential for HD IL-2 to be effective after ICB therapies. The next step would be to look at combination as well as proper sequencing of these immunotherapies to determine the efficacy and the most optimal sequencing [J Clin Oncol. 2015;33(suppl). Abstract 3053].

ITO How do you think these findings will impact the decision of treatment sequencing?

Dr Buchbinder These findings answered our questions concerning the options for mM and mRCC patients who do not respond to ICB and if we should be combining HD IL-2 with these new immunotherapies. These data show that HD IL-2 remains as a very effective and viable treatment option for patients who have progression of their disease on ICB treatment.

ITO Thank you for your time today, and please accept our wishes for continued success in your research endeavors.

Dr Buchbinder Thank you very much.

Dr Buchbinder is Instructor of Medicine at Harvard Medical School and a Medical Oncologist at Dana-Farber Cancer Institute specializing in melanoma, immunotherapies, and targeted therapies.

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